Drug-Resistant Epilepsy: Consensus Definition by ILAE Task Force

Epilepsia, 51(6):1069–1077, 2010
doi: 10.1111/j.1528-1167.2009.02397.x
SPECIAL REPORT
Definition of drug resistant epilepsy: Consensus
proposal by the ad hoc Task Force of the ILAE Commission on
Therapeutic Strategies
*1Patrick Kwan, yAlexis Arzimanoglou, zAnne T. Berg, xMartin J. Brodie,
{W. Allen Hauser, #2Gary Mathern, **Solomon L. Moshé, yyEmilio Perucca, zzSamuel Wiebe,
and xx2Jacqueline French
*Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital,
Hong Kong, China; yInstitute for Children and Adolescents with Epilepsy-IDEE, University Hospital of Lyon (HCL) and Inserm U821,
Lyon, France; zDepartment of Biology, Northern Illinois University, DeKalb, Illinois, U.S.A.; xEpilepsy Unit, Western Infirmary,
Glasgow, United Kingdom; {GH Sergievsky Center, Columbia University, New York, New York, U.S.A.; #Department of
Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California, U.S.A.; **The Saul R. Korey
Department of Neurology, Dominick P. Purpura Department of Neuroscience and Department of Pediatrics, Albert Einstein College
of Medicine, Bronx, New York, U.S.A.; yyClinical Trial Center, Institute of Neurology IRCCS C. Mondino Foundation, and
Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; zzDepartment of Clinical Neurosciences,
University of Calgary, and Hotchkiss Brain Institute, Calgary, Alberta, Canada; and xxNYU Comprehensive Epilepsy Center,
New York, New York, U.S.A.
SUMMARY
To improve patient care and facilitate clinical research,
the International League Against Epilepsy (ILAE)
appointed a Task Force to formulate a consensus definition of drug resistant epilepsy. The overall framework of
the definition has two ‘‘hierarchical’’ levels: Level 1 provides a general scheme to categorize response to each
therapeutic intervention, including a minimum dataset of
knowledge about the intervention that would be needed;
Level 2 provides a core definition of drug resistant
epilepsy using a set of essential criteria based on the
categorization of response (from Level 1) to trials of
Although the concept of drug resistant (often used interchangeably with ‘‘medically refractory/intractable’’ or
‘‘pharmacoresistant’’) epilepsy may appear self-explanatory and intuitive, a precise definition has remained elusive. This has resulted in diverse criteria used by different
clinicians and researchers, or even a lack of explicit criteria
in some cases, rendering it difficult to compare findings
Accepted September 20, 2009; Early View publication November 3,
2009.
Address correspondence to Dr. Patrick Kwan, Department of Medicine
and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China. Email: [email protected]
1
Chair of Task Force.
2
Co-chairs of Commission on Therapeutic Strategies.
Wiley Periodicals, Inc.
ª 2009 International League Against Epilepsy
antiepileptic drugs. It is proposed as a testable hypothesis
that drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and
used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. This definition can be further refined when new
evidence emerges. The rationale behind the definition
and the principles governing its proper use are discussed,
and examples to illustrate its application in clinical practice are provided.
KEY WORDS: Epilepsy, Drug resistance, Refractory,
Intractable, Definition, ILAE.
across studies and to make practice recommendations
(Perucca, 1998; Tanganelli & Regesta, 1999; Berg et al.,
2006; Kwan & Brodie, 2006; Arzimanoglou & Ryvlin,
2008). In response to this situation, the International League Against Epilepsy (ILAE) appointed a Task Force under
the Commission on Therapeutic Strategies to formulate a
proposal for a consensus definition of drug resistant epilepsy. The Task Force comprised members with diverse
expertise, including epidemiology, adult and pediatric
epileptology, neurosurgery, clinical pharmacology, and
clinical trial design. Pertinent literature and discussion at
relevant workshops (Kahane et al., 2008) were considered.
This report sets out the proposed definition, the rationale
behind it, the principles governing its proper use, and
examples to illustrate its application in clinical practice.
The report was circulated to all ILAE Commissions for
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P. Kwan et al.
comment and was approved by the Executive Committee
of the ILAE during the 28th International Epilepsy Congress in Budapest, Hungary, June 28th to July 2nd, 2009. It
should be emphasized that given the paucity of high quality
data on the long-term prognosis of epilepsy, the proposed
definition should not be regarded as a foregone conclusion,
but is intended to represent a consensus opinion that needs
to be tested in rigorous prospective studies and refined as
new evidence emerges.
Any definition of drug resistant epilepsy should be understood and applied within the context of its intended use,
because different definitions may be required for different
purposes. The primary goal of this consensus definition is to
improve patient care and facilitate clinical research. As
such, by setting out the minimum criteria for defining drugresistant epilepsy, it aims to serve as a working definition
that is pragmatic and applicable for everyday clinical management. Fulfillment of the definition in a patient should
prompt a comprehensive review of the diagnosis and management, preferably by an epilepsy center. In addition, by
applying the definition, practitioners (and patients) can be
alerted to the type of information that should be collected
during clinical consultation.
The primary target users of the definition are medical
practitioners at all health care levels (including primary care
practitioners, general neurologists, and epileptologists)
directly involved in the clinical care of people with epilepsy.
With the appropriate information collected on treatment
response, we believe the definition may aid nonspecialists
in recognizing patients with drug resistant epilepsy for
prompt referral to specialist centers for evaluation. Other
target users are clinical researchers, because adoption of a
consensus definition will facilitate comparison and meaningful synthesis of results across studies. The definition may
also be valuable to patients and their caretakers, as well as
other interest groups such as scientists in basic research,
government regulators, legislators, health care administrators, insurers, educators, and employers.
Framework of Definition
The overall framework of the definition comprises two
‘‘hierarchical’’ levels: Level 1 provides a general template
or scheme to categorize outcome to each therapeutic intervention (whether pharmacologic or nonpharmacologic),
including a minimum dataset about the intervention that
would be needed for such purpose. Broadly, the categories
of outcome include ‘‘seizure-free,’’ ‘‘treatment failure,’’ and
‘‘undetermined,’’ which are elaborated below. Level 1
forms the basis for Level 2, which provides a core definition
of drug resistant epilepsy based on how many ‘‘informative’’ trials of antiepileptic drugs (AEDs) resulted in a
‘‘treatment failure’’ outcome (as defined in Level 1). This
core definition may then be adapted, where appropriate, for
specific purposes or clinical scenarios.
Epilepsia, 51(6):1069–1077, 2010
doi: 10.1111/j.1528-1167.2009.02397.x
Level 1: Categorization of
Outcome to a Therapeutic
Intervention
There are many dimensions in a patient’s outcome to a
given therapeutic intervention. The categorization scheme
should be simple and practical, rather than exhaustive, to
facilitate its use across a broad range of clinical and research
settings. Therefore, the proposed scheme contains the two
most clinically relevant outcome dimensions, namely, seizure control and occurrence of adverse effects (Table 1).
Outcomes to a given intervention are categorized based on
whether it rendered the patient seizure-free (Category 1) or
not (Category 2). For the outcome to fall into either category, the intervention must be ‘‘appropriate’’ and ‘‘adequate,’’ each of which is defined in subsequent text of this
article. Otherwise, the outcome is designated as undetermined (Category 3). Each category is then subdivided into
A, B, and C, based on outcome with respect to adverse
effects. This subdivision is included even though it does not
contribute to the definition of drug resistance, because there
is an important clinical difference between a seizure-free
patient without any adverse effects, and one who is seizure
free at the expense of substantial adverse effects. Capturing
this information may aid clinicians in deciding interventions. The appropriate application of the scheme is based on
the following assumptions and provisions.
Appropriateness of intervention
To be regarded as an intervention in the scheme, it must
be ‘‘appropriate’’ for the patient’s epilepsy and seizure type.
An ‘‘appropriate’’ intervention should have previously been
shown to be effective, preferably in randomized controlled
studies, which provide the highest level of evidence. Instead
of listing all ‘‘appropriate’’ interventions, it is suggested that
Table 1. Scheme for categorizing outcome of an
intervention for epilepsy
Outcome dimensiona
Seizure
control
Occurrence of
adverse effects
1. Seizure-free
A. No
B. Yes
C. Undetermined
A. No
B. Yes
C. Undetermined
A. No
B. Yes
C. Undetermined
2. Treatment failure
3. Undetermined
Outcome
category
1A
1B
1C
2A
2B
2C
3A
3B
3C
a
See text for definitions of ‘‘seizure-free,’’ ‘‘treatment failure,’’ and ‘‘undetermined.’’ The numeric and alphabetic nomenclature of categories does not
imply gradation or hierarchy.
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Definition of Drug Resistant Epilepsy
anyone using this scheme justify their choices in this regard.
For instance, ethosuximide would usually not be considered
an appropriate intervention for focal seizures. Under most
circumstances, a trial of this drug in a patient with focal epilepsy would not ‘‘count’’ toward being defined as ‘‘drug
resistance.’’
‘‘Adequate/informative’’ versus ‘‘uninformative’’ trial
In addition to being ‘‘appropriate,’’ the intervention must
have been applied ‘‘adequately’’ for a valid assessment of
the treatment outcome. In general, this requires application
of the intervention at adequate strength/dosage for a sufficient length of time. This may not be the case in some circumstances, for example, when a drug is withdrawn before
it has been titrated to its clinically effective dose range
because of an adverse effect. Although the drug has ‘‘failed’’
(i.e., it is not a suitable intervention for the patient), the
‘‘failure’’ was not because of lack of efficacy for seizure
control. Such an outcome may have little bearing on the efficacy of other AEDs and generally is not considered as part
of ‘‘drug resistance’’ per se. In these situations, outcome of
the intervention in terms of seizure control should be categorized as ‘‘undetermined.’’ If the patient is lost to followup before outcome to an intervention can be evaluated, then
seizure control and occurrence of adverse effects will both
be considered ‘‘undetermined.’’
Given the wide interindividual variation in the doses
required to achieve seizure freedom (Kwan & Brodie,
2001), it is difficult to rigidly define the ‘‘clinically effective
dose range’’ for each AED. This is further confounded by
multiple internal and external factors, including the setting
in which the AED is used (monotherapy or polytherapy),
the age of the patient, and the presence of hepatic or renal
impairment, which may affect drug clearance. As an example, for adults, reference may be made to the World Health
Organization (WHO)’s defined daily dose (DDD), which is
the assumed average maintenance dose per day for a drug
used for its main indication (World Health Organization,
2008). It is important to note that there should be a documented attempt to titrate the dose to a target clinically effective dose range, particularly for AEDs, the tolerability of
which is strongly dependent upon gradual titration (Perucca
et al., 2001).
Table 2 lists the minimum dataset required to determine
whether the trial of an intervention is informative in an individual patient. In the absence of this dataset, the response
should be considered undetermined. In practice, the data
may be adequate for assessing adverse effects but not seizure control, or vice versa. This is acknowledged in the
scheme in Table 1.
Seizure freedom and treatment failure
Lifelong seizure freedom without adverse effects can be
considered the most clinically relevant outcome of any
intervention for epilepsy (Sillanp et al., 2004; Vickrey
Table 2. Minimum dataset required to determine
whether the trial of a therapeutic intervention is
informative
Nature of the intervention (e.g., type of drug, in the case of antiepileptic
drug treatment)
Mode of application (e.g., formulation, dose, dosing interval, and patient’s
compliance in case of an antiepileptic drug)
Duration of exposure
Occurrence of seizures and adverse effects during the trial period
Whether there was any effort to optimize dose
Reason(s) for discontinuation (if applicable)
Unsatisfactory seizure control
Adverse effects
Long-term seizure freedom
Psychosocial reasons, for example, planning for pregnancy
Administrative reasons, for example, lost to follow up
Financial issues, for example, cannot afford treatment
Patient/caretaker preference
Other reasons
et al., 1995; Jacoby et al., 2007; Tllez-Zenteno et al.,
2007). Therefore, under the scheme, seizure outcome is
dichotomized into seizure-free (Category 1) or treatment
failure (Category 2). The term ‘‘seizure-free’’ refers to freedom from all seizures, including auras. It is acknowledged
that different seizure types in different individuals may be
associated with variable degrees of impact, which is a matter of appreciation and would be taken into account by the
treating clinician when deciding the most appropriate course
of action for the patient. Therefore, for practicality, occurrence of any seizure is regarded to indicate failure of the
treatment to lead to seizure freedom.
Breakthrough seizures that occur in temporal proximity
to potentially seizure provoking external factors such as
sleep deprivation, menstruation, intercurrent febrile illness,
and so on, pose difficulties in categorization because the
causal association between the external factor and the seizure is often uncertain. In general, seizures that occur under
these circumstances should still be considered as evidence
of inadequate seizure control and hence treatment failure,
but seizure relapse due to poor treatment compliance should
not.
In deliberating what constitutes an adequate period without seizures for a patient to be regarded as ‘‘seizure-free,’’
two main factors were considered. First, the duration of
follow-up required to determine whether a therapeutic
intervention has had an appreciable impact on seizure
occurrence is dependent on the preintervention seizure
frequency. For instance, it would not be surprising for a
patient with only one seizure in the previous year to remain
seizure-free for the next 6 months after starting a new intervention, but it would be premature and unwarranted to claim
that the therapeutic intervention is responsible for a patient’s
freedom from seizures until sufficient time has passed.
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The ‘‘rule of three’’ for calculating confidence intervals
for zero events can be used in this setting (Hanley &
Lippman-Hand, 1983). To be 95% certain that a patient’s
seizure frequency has at very least decreased (i.e., there has
been some therapeutic effect), a seizure-free duration that is
at least three times the longest interseizure interval prior to
starting a new intervention would need to be observed. For
example, if prior to the intervention the patient had intervals
without seizures of up to 6 months, a seizure-free period of
18 months would be required to reasonably conclude that
his seizure frequency is lower than that prior to the intervention. It should be noted that, in theory, patients with even
more infrequent seizures would have to be followed up for
many years to determine whether their seizures had truly
come under control. This is not practical, either in research
or clinical settings. For this reason we recommend that three
times the longest interseizure interval be used as an indicator of positive treatment response. Given that an initiation or
change of intervention regimen is often not indicated for seizures occurring less than once per year, the longest preintervention interseizure interval should be determined from
seizures occurring within the preceding 12 months. For
practical purpose, interseizure interval should be derived
according to days on which one or more seizure has
occurred. Obviously, at least two seizures must have been
documented to determine the preintervention interseizure
interval; therefore, this approach cannot be applied to a
patient treated after a single seizure.
The other main consideration is the need to document a
sustained response that is clinically meaningful. Studies
including patients treated medically (Sillanp & Shinnar,
2005; Jacoby et al., 2007) or surgically (Markand et al.,
2000; Spencer et al., 2007) show that absolute seizure freedom, usually taken as at least 12 months, is the only relevant
outcome consistently associated with meaningful improvement in quality of life. In a community-based survey,
patients with one or more seizures over the last 2 years had
higher levels of anxiety and depression, greater perceived
stigma and impact of epilepsy, and lower employment rates
than did those who were seizure-free (Jacoby et al., 1996).
In many countries, having even one seizure per year poses
restrictions on driving (Fisher et al., 1994; Berg & Engel,
1999). Therefore, there was consensus that seizure-free
duration should be at least 12 months.
Based on the preceding consideration, seizure freedom
(Category 1 outcome) is defined as freedom from seizures
for a minimum of three times the longest preintervention interseizure interval (determined from seizures occurring
within the past 12 months) or 12 months, whichever is
longer. On the other hand, treatment failure (Category 2 outcome) is defined as recurrent seizure(s) after the intervention has been adequately applied (as defined earlier). If a
patient has been seizure-free for three times the preintervention interseizure interval but for <12 months, seizure control should be categorized as ‘‘undetermined.’’ However, if
Epilepsia, 51(6):1069–1077, 2010
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the patient experiences another seizure before the end of the
12-month period, the treatment is considered ‘‘failed,’’ even
though the seizure frequency has reduced compared with
baseline. We acknowledge that a therapeutic intervention
may lead to a clinically meaningful reduction in seizure frequency (or severity) that stops short of seizure freedom. Categorization of such a response may be considered at a later
date for incorporation into the scheme.
Occurrence of adverse effects
By adapting the WHO’s definition of adverse drug reaction (World Health Organization, 1972), an adverse effect
to any therapeutic intervention for epilepsy may be defined
as ‘‘any response to an intervention which is noxious and
unintended, and which occurs when the intervention is
applied with modalities normally used in humans for the
treatment of epilepsy.’’ The WHO definition has generally
been interpreted as implying that there should be no error in
the use of the intervention (Leape, 1995; Edwards &
Aronson, 2000), an important consideration that is consistent with the concept of ‘‘appropriateness’’ of intervention,
as already discussed.
Assessing adverse effects is fraught with difficulties, and
some elements of subjectivity are unavoidable. Critical
issues in the assessment are the methodology used to detect
and quantify adverse effects, and the criteria applied to
establish the causality link with the applied intervention. In
particular, relying on unstructured interviews and a general
medical examination may lead to underestimation of
adverse effects, whereas the use of checklists and questionnaires can lead to overestimation (Baker et al., 1998;
CarreÇo et al., 2008). Some important adverse effects, such
as vigabatrin-induced visual field defects, may only be identifiable with specialized laboratory tests (Wild et al., 2007).
Algorithms for causality assessment have been developed
(Karch & Lasagna, 1977; Edwards & Aronson, 2000). Even
when causality has been established, assessing the clinical
impact of an adverse effect on the individual’s well being or
quality of life is a challenging task. In most clinical situations, however, treating physicians can make a reasonable
subjective judgment based on results of medical examination and interviews with patient and family members, and
we suggest that such judgment be applied when categorizing
the presence or absence of adverse effects in response to an
intervention.
Other dimensions of outcome
For practical purposes, other dimensions of outcome are
not included in the current scheme, but their importance is
recognized and they may be incorporated into future
schemes. These dimensions may include factors such as
psychosocial outcomes and level of patient satisfaction. A
variety of quality of life scales have been developed and
are widely applied in research settings (Leone et al.,
2005). From a patient-centered care perspective, patients’
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Definition of Drug Resistant Epilepsy
satisfaction with an intervention should be the final arbiter
in defining its success or failure. Patients’ satisfaction
extends beyond measurement of seizure control, adverse
effects, or quality of life scores, and may be influenced by a
broad range of internal and external variables, such as, in
the case of epilepsy surgery, preoperative expectations,
postoperative affect, ability to discard the sick role, subsequently obtaining employment, and perceived success
(Wass et al., 1996; Wilson et al., 1999; Reid et al., 2004;
Chin et al., 2006). Although the construct of patient satisfaction with an intervention is multifaceted and complex, it
has been successfully evaluated using simple, single-item,
or few-item rating scales, such as dichotomous yes/no questions, or graded point scales. Clinicians may be encouraged
to include one of these measures in their assessment when
assessing success or failure of an intervention and in clinical
decision making.
Level 2: Definition of
Drug Resistant Epilepsy
Drug responsiveness of a patient’s epilepsy should be
regarded as a dynamic process rather than a fixed state.
Instead of being constant, the course of epilepsy sometimes
fluctuates (Berg et al., 2009), and apparent changes in
responsiveness to AED treatment may merely represent
shifts in the pathophysiology of the underlying disorder.
The classification of a patient’s epilepsy as drug resistant at
a given point in time is valid only at the time of the assessment and does not necessarily imply that the patient will
never become seizure-free on further manipulation of AED
therapy (Huttenlocher & Hapke, 1990; Berg et al., 2001,
2006; Callaghan et al., 2007; Luciano & Shorvon, 2007;
Schiller & Najjar, 2008).
The number of AEDs that needs to have failed for the epilepsy to be defined as drug resistant was extensively debated
within the Task Force. An implicit assumption in any definition is that seizure freedom will not or is very unlikely to be
attained with further manipulation of AED therapy. Therefore, any definition must be based on an assessment of the
probability of subsequent remission after each drug failure.
Ideally, the evidence should be derived from large-scale,
prospective, long-term, population-based studies including
both adults and children at the point of diagnosis or treatment initiation, and should be based on an assessment of
outcome after failure of successive informative AED trials.
Few, if any, studies in the literature meet such requirement.
Observational cohort studies of newly diagnosed epilepsy in
adults (Kwan & Brodie, 2000; Mohanraj & Brodie, 2006)
and children (Arts et al., 2004) suggest that once a patient
has failed trials of two appropriate AEDs, the probability of
achieving seizure freedom with subsequent AED treatments
is modest. Recent studies appear to suggest that a proportion
of these patients may still become seizure-free with subsequent drug manipulation (Callaghan et al., 2007; Luciano &
Shorvon, 2007), but these studies were retrospective and
sampled prevalent cases, and did not take into account the
reasons for failure which, as already discussed, may indicate
that the AEDs have not been adequately tried. A recent
report from a prospective study in children documented that
although many patients who had failed two informative trials of AEDs had periods of seizure freedom with further
drug trials, lasting remission remained elusive (Berg et al.,
2009).
On the basis of a careful deliberation of the available evidence, building on Level 1 of the definition framework, for
operational purposes, the following definition is proposed:
Drug resistant epilepsy may be defined as failure of adequate trials of two tolerated and appropriately chosen
and used AED schedules (whether as monotherapies or
in combination) to achieve sustained seizure freedom.
It should be stressed that the consensus to adopt the failure of two (rather than greater numbers) AED schedules in
the definition represents a testable hypothesis and aims to
avoid unnecessary delay in evaluation, and may be revised
as more high quality data become available.
In addition to number of AEDs failed, two other elements
are most commonly included in definitions of drug resistant
epilepsy in the literature, namely, the frequency of seizures
and duration of follow-up. In the proposed definition, ‘‘failure’’ and ‘‘sustained seizure freedom’’ are as defined in
Level 1 (categorization of intervention outcome) of the definition framework, which already incorporates seizure frequency and treatment duration, so that separate criteria for
these elements are redundant. Applying the categorization
of intervention outcome (Table 1), drug resistance is
defined as having Category 2 outcome for trials of at least
two AEDs (monotherapies or in combination) without a
Category 1 outcome on the drug(s) currently taken. Drug
resistance should be defined only by informative trials, that
is, the two AEDs should have been appropriately chosen
and adequately tried, and that none of the outcomes that will
be counted toward the two drug failures should be ‘‘undetermined.’’ In other words, some patients may ‘‘fail’’ many
AEDs before they fail two that are ‘‘appropriate’’ and in a
way that is ‘‘informative.’’
Drug-responsive epilepsy and apparent fluctuation in
drug responsiveness
It follows from Level 1 of the definition framework that a
person’s epilepsy can be classified as ‘‘drug responsive’’ if
he/she is having a Category 1 outcome to the current AED
regimen, that is, he/she has been seizure-free for a minimum
of three times the longest pretreatment interseizure interval,
or 12 months, whichever is longer.
During its long and sometimes fluctuating course a person’s epilepsy may not fulfill the definition criteria for
either drug resistant or drug-responsive epilepsy at certain
time points. In such circumstances, drug responsiveness
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P. Kwan et al.
Table 3. Examples of how the definition framework can be applied in different clinical scenarios
Level 2—classification
of drug responsiveness
of epilepsy
Notes
Narrative drug
Patient history
Level 1—categorization
of treatment outcome
1
One current drug with
seizure-free outcome
(Cat. 1A)
Drug responsive
One current drug with
seizure-free outcome
(Cat. 1B)
Drug responsive
2
3
4
5
6
A patient had one seizure in January
2006 and two seizures in October
2006. After starting treatment in
November 2006 he has been seizure
free for 30 months with no adverse
effect
A 16-year-old patient was started on
valproate 2 years ago after
experiencing two seizures in 6 months,
and has been seizure-free since with
mild sedation. He reports a history
of an apparently nonfebrile
convulsive seizure when he was
6 years of age
One previous drug with
Drug resistant
A 40-year old man was diagnosed to
undetermined outcome
have partial epilepsy 20 years ago.
(Cat. 3C). Two current drugs
He reported ‘‘I was on phenytoin
with treatment failure outcome
initially for a short period, it didn’t
(Cat. 2)
work and they took me off.’’ He was
then given an adequate trial of
carbamazepine but continued to have
monthly seizures. Levetiracetam
was added 1 year ago and tried
adequately. He now has seizures once
every 3 months
One current drug with
Undefined
A patient was newly started on
undetermined outcome
carbamazepine after two partial
(Cat. 3)
seizures in 9 months. He has had no
seizures for 12 months since
A 16-year-old girl was started on
carbamazepine a week after she
had a tonic–clonic seizure in the
morning, with a history (not
recognized by her doctor at the
time) of jerks over the past
3 months. The jerks got
worse after 2 months on
carbamazepine 800 mg/day.
EEG later showed generalized
polyspike and wave discharge. She
was diagnosed to have juvenile
myoclonic epilepsy and was
switched to lamotrigine, which
was stopped after 2 weeks
(dosage at the time, 50 mg/day)
because of a rash. She is now on
valproate 2 g/day for 3 months,
but occasional jerks continue
A patient is having more than one
seizure per day for 3 months despite
adequate trials of four appropriate
AEDs. Patient is taking one drug
currently
One previous inappropriate
drug. One previous drug
with undetermined outcome
(Cat. 3B). One current drug
with treatment failure
outcome (Cat. 2)
Undefined
Three previous drugs and one
current drug with treatment
failure outcome (Cat. 2)
Drug resistant
The longest pretreatment interseizure
interval was 9 months (January–October
2006). The patient has had no seizure
for more than three times the pretreatment
interseizure interval and for more than
12 months
The longest pretreatment interseizure
interval was 6 months. The patient has
had no seizure for more than three times
the pretreatment interseizure interval and
for more than 12 months. The seizure that
occurred at 6 years of age (more than
12 months prior to starting treatment) is
not relevant to determining the responsive
ness of his current epilepsy
Outcome of phenytoin treatment was
undetermined because of lack of sufficient
data (see Table 2). Nonetheless, he has
failed informative trials with two appropriate
AEDs. Treatment with levetiracetam is
considered failed because despite reduction
in seizure frequency, seizure free duration
is <12 months
The pretreatment interseizure interval was
9 months. Although the patient has had no
seizure for 12 months, the duration is less
than three times the pretreatment
interseizure interval, hence outcome to
treatment is undetermined and drug
responsiveness of epilepsy is undefined
Carbamazepine is recognized to exacerbate
myoclonic seizures and, in this case, is not
considered an appropriate treatment for
the patient’s epilepsy syndrome.
Lamotrigine and valproate are appropriate
treatments, but outcome in terms of seizure
control of lamotrigine is undetermined
because it was stopped due to an adverse
effect during titration, before a dose range
usually regarded as optimal could be
reached. Thus the patient has failed only
one drug (valproate) so far, and the drug
responsiveness of her epilepsy remains
undefined
The patient has failed more than two
appropriate AEDs
Continued
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Definition of Drug Resistant Epilepsy
Table 3. Continued.
Patient
Narrative drug history
6
After adding drug X, patient 6 has had
no seizure for 8 months
6
With further follow-up patient 6 has
had no seizure for 24 months
6
Patient 6 has two seizures within
1 month
6
Two more appropriate AEDs are
added at adequate dosage but
patient 6 continues to have seizures
once per month
Level 2—classification
of drug responsiveness
of epilepsy
Level 1—categorization
of treatment outcome
Four previous drugs with
treatment failure outcome
(Cat. 2). One current drug
with undetermined outcome
(Cat. 3)
Four previous drugs with
treatment failure outcome
(Cat. 2). One current drug
with seizure-free outcome
(Cat. 1)
Four previous drugs and one
current drug with treatment
failure outcome (Cat. 2)
Four previous drugs and three
current drugs with treatment
failure outcome (Cat. 2)
Notes
Drug resistant
Outcome of treatment with drug X is
undetermined and the epilepsy remains
drug resistant because the patient has not
been seizure-free for 12 months
Drug responsive
The patient has had no seizures for more
than three times the pretreatment
interseizure interval and for more than
12 months
Undefined
The patient is no longer seizure free,
treatment of drug X is failed, but the
‘‘clock’’ is ‘‘reset’’ for considering the
epilepsy to be drug resistant again in future
after it has been drug responsive. Thus at
present the epilepsy does not fulfill the
criteria of drug resistant (unless the patient
fails at least one further drug after the
relapse)
After the relapse the patient has failed
more than two adequate trials of
appropriate AEDs
Drug resistant
AED, antiepileptic drug; EEG, electroencephalography.
should be temporarily classified as ‘‘undefined.’’ This
occurs, for instance, in a newly diagnosed patient who has
not experienced the duration required for defining seizure
freedom, or in a patient who has failed informative trials
of less than two AEDs.
Other scenarios that pose difficulty in classification
occur when there appears to be a change in drug responsiveness of the epilepsy during its dynamic course. In
these scenarios the classification should be reviewed and
revised accordingly. For instance, a patient with drugresistant epilepsy stops having seizures upon receiving a
new AED regimen but the duration does not yet meet the
criteria for defining seizure freedom. For clarity, it is proposed that outcome of the individual drug (Level 1)
should be categorized as ‘‘undetermined’’ and the overall
drug responsiveness (Level 2) should remain as drug
resistant unless and until sufficient time has passed to
reclassify the epilepsy as drug responsive (i.e., seizurefree for three times pretreatment interseizure interval, or
12 months, whichever is longer).
In the opposite scenario, seizure relapses in a seizure-free
patient. In this situation clearly the epilepsy is no longer
drug responsive, but it can only be considered drug resistant
if it subsequently meets the criteria for resistance. It is proposed that, if only one seizure has recurred, the outcome of
the individual drug (Level 1) should be categorized as
‘‘undetermined’’ and the overall drug responsiveness
(Level 2) should be classified as ‘‘undefined.’’ If two
seizures have recurred, outcome to the individual drug(s)
should be categorized as treatment failure, and the overall
drug responsiveness remains ‘‘undefined.’’ If an additional
AED is adequately tried and failed, then the epilepsy is
redefined as drug resistant. If the patient has had no further
seizure for three times the interseizure interval (of the
relapsed seizures) or 1 year, whichever is longer, the epilepsy is redefined as drug responsive. It is proposed that this
classification approach also applies to the scenarios where
the epilepsy had been drug resistant before the patient
became seizure free. Because there is a paucity of data on
the seizure pattern in such scenarios it is acknowledged that
such a classification approach is largely empirical and needs
to be tested for its validity in prospective studies.
Application of the Definition
in Specific Scenarios
We recommend application of the consensus definition
to diverse clinical and research scenarios. For instance,
the core definition may be applied, after adaptation, to the
selection of candidates for epilepsy surgery or for referral
to an epilepsy center for a comprehensive evaluation.
Obviously, because presurgical evaluation and surgery
Epilepsia, 51(6):1069–1077, 2010
doi: 10.1111/j.1528-1167.2009.02397.x
1076
P. Kwan et al.
itself may entail risks, the decision to offer surgical treatment requires individual risk–benefit analysis that
includes an assessment of possible success with additional
trials of AEDs. The proposed definition also has implications for the design of randomized drug trials and should
prove useful in the selection of patients for such trials, in
which the criteria for considering a patient drug resistant
are often poorly described. In this setting, a standard definition of drug resistance is important to ensure that results
are comparable across trials. It would be particularly
important to have clear documentation of previous AEDs
that failed to control seizures, excluding those ‘‘uninformative’’ trials, and including the reasons for failure.
Glossary
Adverse effect
Appropriate
intervention
Drug responsiveness
Drug resistant
epilepsy
Conclusion
The development of the proposed consensus definition
was driven by the growing need among medical practitioners and clinical researchers to adopt a common language
in recognizing drug resistant epilepsy in the face of rapidly expanding therapeutic options. The definition aims to
describe responsiveness to AED therapy but does not
address the possible determining factors. Indeed, it is
hoped that adoption of a common definition of drug resistance by researchers will facilitate the identification of
such factors. During the process of formulating the definition, we were aware of deficiencies in the knowledge
base, and inevitably assumptions were made that require
testing and validation in future studies. In particular, there
is a need for better documentation of the often fluctuating
pattern of seizure occurrences and of the time course of
treatment response in newly diagnosed patients. These
data are required to provide a better understanding of the
dynamic relationships among the various dimensions of
treatment outcome. The proposed definition, therefore, is
not intended to be prescriptive but represents a working
framework. Clinicians and researchers should exercise
their judgment in interpreting the principles described in
this report when applying the definition to diverse settings. Some examples of how to apply the definition in
various clinical scenarios are illustrated in Table 3.
Because, as stated by Voltaire, the 18th century French
Enlightenment writer and philosopher, ‘‘the perfect is the
enemy of the good,’’ we hope that this consensus definition will serve its pragmatic purpose. Its adoption by the
epilepsy community will allow future testing and refinement as and when new evidence emerges.
Acknowledgments
The work of the Task Force was supported by the ILAE, which provided
funding and approved the report. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this
report is consistent with those guidelines.
Disclosure: None of the authors has any conflict of interest to disclose.
Epilepsia, 51(6):1069–1077, 2010
doi: 10.1111/j.1528-1167.2009.02397.x
Drug-responsive
epilepsy
Intervention
Seizure
freedom
Treatment
failure
Treatment
outcome
Undefined drug
responsiveness
Undetermined
outcome
Uninformative trial
Any response to an intervention that is
noxious and unintended, and which occurs
when the intervention is applied with
modalities normally used in humans for the
therapy of a disease
An intervention that has been shown to be
safe and effective with appropriately
documented evidence
Whether the epilepsy is drug resistant, drug
responsive, or neither (undefined)
Epilepsy in which seizures persist and seizure
freedom is very unlikely to be attained with
further manipulation of AED therapy. In the
current proposal, it is defined as ‘‘failure of
adequate trials of two tolerated and
appropriately chosen and used AED
schedules (whether as monotherapies or in
combination) to achieve sustained seizure
freedom’’
Epilepsy in which the patient receiving the
current AED regimen has been seizure-free
for a minimum of three times the longest
preintervention interseizure interval or
12 months, whichever is longer
A substance, device, or action applied to an
epilepsy patient with the primary aim of
reducing or preventing the occurrence of
seizures
Freedom from all types of seizures for
12 months or three times the preintervention
interseizure interval, whichever is longer
The outcome whereby the patient did not
attain seizure freedom after an informative
trial of an intervention
Effect of an intervention as categorized by
seizure control and occurrence of adverse
effects
Drug responsiveness that cannot be classified
as either drug responsive or drug resistant
The situation whereby there is insufficient
information to determine the outcome of
an intervention in terms of seizure control
or occurrence of adverse effects, or both
An intervention for which there is insufficient
information to determine its outcome in an
individual patient
References
Arts WF, Brouwer OF, Peters AC, Stroink H, Peeters EA, Schmitz PI, van
Donselaar CA, Geerts AT. (2004) Course and prognosis of childhood
epilepsy: 5-year follow-up of the Dutch study of epilepsy in childhood.
Brain 127:1774–1784.
Arzimanoglou A, Ryvlin P. (2008) Towards a clinically meaningful definition of drug-resistance. In Kahane P, Berg A, Lçscher W, Nordli D, Perucca E (Eds) Progress in Epileptic Disorder (Volume 7): Drugresistant epilepsies. John Libbey Eurotext, Montrouge, France, pp. 1–6.
Baker GA, Camfield C, Camfield P, Cramer JA, Elger CE, Johnson AL,
Martins da Silva A, Meinardi H, Munari C, Perucca E, Thorbeke R.
1077
Definition of Drug Resistant Epilepsy
(1998) Commission on Outcome Measurement in Epilepsy, 1994–
1997: Final report. Epilepsia 39:213–231.
Berg AT, Engel J Jr. (1999) Restricted driving for people with epilepsy.
Neurology 52:1306–1307.
Berg AT, Shinnar S, Levy SR, Testa F, Smith-Rapaport S, Beckerman B.
(2001) Early development of intractable epilepsy in children: a prospective study. Neurology 56:1445–1452.
Berg AT, Vickrey BG, Testa FM, Levy SR, Shinnar S, DiMario F, Smith S.
(2006) How long does it take epilepsy to become intractable? A prospective investigation. Ann Neurol 60:73–79.
Berg AT, Levy SR, Testa FM, D’Souza R. (2009) Remission of epilepsy
after 2 drug failures in children: a prospective study. Ann Neurol
65:510–519.
Callaghan BC, Anand K, Hesdorffer D, Hauser WA, French JA. (2007)
Likelihood of seizure remission in an adult population with refractory
epilepsy. Ann Neurol 62:382–389.
CarreÇo M, Gil-Nagel A, Snchez JC, Elices E, Serratosa JM, SalasPuig J, Villanueva V, Porcel J. (2008) Strategies to detect adverse
effects of antiepileptic drugs in clinical practice. Epilepsy Behav
13:178–183.
Chin PS, Berg AT, Spencer SS, Lee ML, Shinnar S, Sperling MR, Langfitt
JT, Walczak TS, Pacia SV, Bazil CW, Vassar S, Vickrey BG. (2006)
Patient-perceived impact of resective epilepsy surgery. Neurology
66:1882–1887.
Edwards RI, Aronson JK. (2000) Adverse drug reactions: definitions, diagnosis, and management. Lancet 356:1255–1259.
Fisher RS, Parsonage M, Beaussart M, Bladin P, Masland R, Sonnen AE,
Rmillard G. (1994) Epilepsy and driving: an international perspective.
Joint Commission on Drivers’ Licensing of the International Bureau for
Epilepsy and the International League Against Epilepsy. Epilepsia
35:675–684.
Hanley JA, Lippman-Hand A. (1983) If nothing goes wrong, is everything
alright? JAMA 259:1743–1745.
Huttenlocher PR, Hapke RJ. (1990) A follow-up study of intractable seizures in childhood. Ann Neurol 28:699–705.
Jacoby A, Baker GA, Steen N, Potts P, Chadwick DW. (1996) The clinical
course of epilepsy and its psychosocial correlates: findings from a U.K.
Community study. Epilepsia 37:148–161.
Jacoby A, Gamble C, Doughty J, Marson A, Chadwick D; Medical
Research Council MESS Study Group. (2007) Quality of life outcomes
of immediate or delayed treatment of early epilepsy and single seizures.
Neurology 68:1188–1196.
Kahane P, Berg A, Lçscher W, Nordli D, Perucca E. (2008) Drug-resistant
Epilepsies. Progress in Epileptic Disorders, Vol. 7. John Libbey Eurotext, Montrouge, France.
Karch FE, Lasagna L. (1977) Toward the operational identification of
adverse drug reactions. Clin Pharmacol Ther 21:247–254.
Kwan P, Brodie MJ. (2000) Early identification of refractory epilepsy.
N Engl J Med 342:314–319.
Kwan P, Brodie MJ. (2001) Effectiveness of first antiepileptic drug. Epilepsia 42:1255–1260.
Kwan P, Brodie MJ. (2006) Issues of medical intractability for surgical
candidacy. In Wyllie E (Ed.) The Treatment of Epilepsy: Principles and
Practice. 4th ed. Lippincott Williams & Wilkins, Philadelphia,
pp. 983–991.
Leape LL. (1995) Preventing adverse drug events. Am J Health Syst Pharm
52:379–382.
Leone MA, Beghi E, Righini C, Apolone G, Mosconi P. (2005) Epilepsy
and quality of life in adults: a review of instruments. Epilepsy Res
66:23–44.
Luciano AL, Shorvon SD. (2007) Results of treatment changes in patients
with apparently drug-resistant chronic epilepsy. Ann Neurol 62:375–
381.
Markand ON, Salanova V, Whelihan E, Emsley CL. (2000) Health-related
quality of life outcome in medically refractory epilepsy treated with
anterior temporal lobectomy. Epilepsia 41:749–759.
Mohanraj R, Brodie MJ. (2006) Diagnosing refractory epilepsy: response
to sequential treatment schedules. Eur J Neurol 13:277–282.
Perucca E. (1998) Pharmacoresistance in epilepsy. How should it be
defined? CNS Drugs 10:171–179.
Perucca E, Dulac O, Shorvon S, Tomson T. (2001) Harnessing the clinical
potential of antiepileptic drug therapy: dosage optimisation. CNS Drugs
15:609–621.
Reid K, Herbert A, Baker GA. (2004) Epilepsy surgery: patient perceived
long-term costs and benefits. Epilepsy Behav 5:81–878.
Schiller Y, Najjar Y. (2008) Quantifying the response to antiepileptic
drugs: effect of past treatment history. Neurology 70:54–65.
Sillanp M, Haataja L, Shinnar S. (2004) Perceived impact of childhoodonset epilepsy on quality of life as an adult. Epilepsia 45:971–977.
Sillanp M, Shinnar S. (2005) Obtaining a driver’s license and seizure
relapse in patients with childhood-onset epilepsy. Neurology 64:680–
686.
Spencer SS, Berg AT, Vickrey BG, Sperling MR, Bazil CW, Haut S, Langfitt JT, Walczak TS, Devinsky O; Multicenter Study of Epilepsy Surgery. (2007) Health-related quality of life over time since resective
epilepsy surgery. Ann Neurol 62:327–334.
Tanganelli P, Regesta G. (1999) Clinical aspects and bioloogical bases of
drug-resistant epilepsy. Epilepsy Res 34:109–122.
Tllez-Zenteno JF, Dhar R, Hernandez-Ronquillo L, Wiebe S. (2007)
Long-term outcomes in epilepsy surgery: antiepileptic drugs, mortality,
cognitive and psychosocial aspects. Brain 130(Pt 2):334–345.
Vickrey BG, Hays RD, Rausch R, Engel J Jr, Visscher BR, Ary CM, Rogers
WH, Brook RH. (1995) Outcomes in 248 patients who had diagnostic
evaluations for epilepsy surgery. Lancet 346:1445–1449.
Wass CT, Rajala MM, Hughes JM, Sharbrough FW, Offord KP,
Rademacher DM, Lanier WL. (1996) Long term follow up of patients
treated surgically for medically intractable epilepsy: results in 191
patients treated at Mayo Clinic Rochester between July 1972 and March
1985. Mayo Clin Proc 71:1105–1113.
Wild JM, Ahn HS, Baulac M, Bursztyn J, Chiron C, Gandolfo E, Safran
AB, Schiefer U, Perucca E. (2007) Vigabatrin and epilepsy: lessons
learned. Epilepsia 48:1318–1327.
Wilson SJ, Saling MM, Lawrence J, Bladin PF. (1999) Outcome of temporal lobectomy: expectations and the prediction of perceived success.
Epilepsy Res 36:1–14.
World Health Organization. (1972) International Drug Monitoring: the
Role of National Centres. Techn Rep Series WHO, Geneva, p. 498.
World Health Organization Collaborating Centre for Drug Statistics Methodology. (2008) About the ATC/DDD system. Accessed December 1,
2008 at http://www.whocc.no/atcddd/.
Epilepsia, 51(6):1069–1077, 2010
doi: 10.1111/j.1528-1167.2009.02397.x